In 1960, he approached his colleagues Franco Prosperi and Paolo Cavara with the unusual idea of making an "anti-documentary".[2] The result, which premiered in 1962, was Mondo Cane (which roughly translates to "A Dog's World," a minor curse in Italian), a non-narrative compilation of shocking and unusual footage from around the world. It premiered at the 1962 Cannes Film Festival, where it was well-received and even nominated for the Palme d'Or.[5] The theme song, More (Theme from Mondo Cane) by Italian composer Riz Ortolani was nominated for the Academy Award for Best Song in 1963, the year of its premier in the United States.

The success of Mondo Cane inspired an entire genre of documentaries featuring lurid or shocking subjects, which came to be known as Mondo film. Jacopetti and Prosperi (who would become film-making partners for the remainder of Jacopetti's directorial career) went on to make several more entries into this genre, including La donna nel mondo (Women of the World), (with Paolo Cavara) Mondo Cane 2, Africa Addio and the faux-documentary Addio Zio Tom. In the 2003 documentary The Godfathers of Mondo, Jacopetti describes the style they used to make these films: “Slip in, ask, never pay, never reenact.” [2]

During the filming of Africa Addio—which includes footage of intense fighting and mass death in the Mau Mau uprising, the Zanzibar revolution, the Simba Rebellion, and other post-colonial Africa conflicts—the crew was interrogated in Zaire, and arrested and nearly executed in Tanzania, before an army official intervened on their behalf, shouting “Stop — they’re not whites, they’re Italians.”[2] A scene depicting the execution of a Simba rebel during the Simba Rebellion in Republic of the Congo (Léopoldville) resulted in Jacopetti being charged with murder in Italy; he was acquitted after producing documents demonstrating the footage had not been staged for the cameras.[2]

Following the critical and commercial failure of the faux-documentary Goodbye Uncle Tom (Addio Zio Tom) (which reviewer Roger Ebert called "...the most disgusting, contemptuous insult to decency ever to masquerade as a documentary,")[6] Jacopetti and Prosperi attempted a fictional film, 1975's Mondo Candido (a modern version of Candide by French Philosopher Voltaire). Jacopetti went on to write (but not direct) one further documentary, 1981's Fangio: Una vita a 300 all'ora (which follows the career of Formula One driver Juan Manuel Fangio) before returning to print media for the remainder of his career.[2]

Jacopetti died August 17, 2011 at the age of 91. His ashes were interred in the Non-Catholic Cemetery in Rome. Italian press articles had reported that he wished to be buried next to his girlfriend the British actress Belinda Lee, who died in 1961 in a car accident in which Jacopetti was also hurt.[4]

Despite their early success with Mondo Cane, controversy followed Jacopetti and Prosperi's careers. New York Times reviewer Pauline Kael dismissed Mondo Cane, claiming that its advocates were, “too restless and apathetic to pay attention to motivations and complications, cause and effect.”[1] Criticism became even more pronounced with Africa Addio, which Roger Ebert called "brutal, dishonest, and racist" and claims that it "slanders a continent".[7] Ebert's review was not based on the original film but on an edited version for US audiences. This version was edited and translated without the approval of Jacopetti. Indeed, the differences are such that Jacopetti has called this film a "betrayal" of the original idea.[8] Notable differences are thus present between the Italian and English-language versions in terms of the text of the film. Many advocates of the film feel that it has unfairly maligned the original intentions of the filmmakers. Charges of racism and claims that elements of their film were staged or manufactured by the directors plagued them over the years, though they strongly denied both charges.

Jacopetti claimed his intent was to create films that “...would play on the big screen whose subject was reality.”[1] In the 2003 documentary The Godfathers of Mondo, Prosperi went on to claim criticism of their work was due to the fact that, "The public was not ready for this kind of truth." Both directors denied staging anything for their films,[9] with the exception of Mondo Cane 2 which they acknowledge does contain some staged or recreated footage.[10]